Congenital heart disease is the most common of all birth defects, affecting 1 in 100 infants born each year. Many of the complex lesions begin early in fetal life as simple defects that cause abnormal blood flow patterns within the fetal heart, but ultimately result in abnormal development of major cardiac structures. Despite great advances in neonatal cardiac surgery, a child born with congenital heart disease will likely face far greater morbidity and significant risk of premature mortality. Increasingly, these defects can now be identified early in pregnancy (~20 weeks) by fetal echocardiography, allowing consideration of in utero therapy when postnatal outcomes are grim. Certain interventions require in utero open-heart surgery, which in turn necessitates cardiopulmonary bypass support. However, placental dysfunction following fetal bypass remains the primary impediment to clinical translation of fetal cardiac surgery. This placental dysfunction manifests as an increase in placental vascular resistance, deterioration in fetal gas exchange, and redistribution of fetal circulation. Despite continuing efforts since the 1980's, the mechanism(s) leading to increased placental vascular resistance with fetal bypass remain unexplained. As part of our long-term goal to translate fetal cardiac surgery to the clinic, the purpose of this study is to demonstrate that the fetal stress hormone vasopressin is a key mediator and central cause of fetal circulatory dysfunction during, and following fetal cardiac surgery. The stress hormone vasopressin is a potent vasoconstrictor in the fetal/placental circulation capable of increasing placental vascular resistance primarily through its receptors, (V1 &V2) which are present in ovine and human placental tissues. Fetal insults and the highly stressful event of fetal cardiac surgery elicit rapid and profound increases in fetal vasopressin levels, (~100 times baseline). Placental dysfunction following fetal bypass and cardiac surgery share all the classic hallmarks of vasopressin mediated vasoconstriction: increased peripheral vasoconstriction, placental vascular resistance, and centralized fetal circulation, which when uncontrolled, leads to fetal demise. We propose to test the hypothesis that vasopressin mediates the placental and fetal vascular circulatory disturbances seen following fetal bypass using a mid-gestation fetal sheep model. Specific Aim 1 tests the hypothesis that selective V1 vasopressin receptor antagonism prevents increased placental vascular resistance and improves fetal gas exchange with fetal cardiac surgery and bypass. Specific Aim 2 defines the mechanism(s) of vasopressin receptor actions in the placenta that cause increased placental vascular resistance and placental dysfunction with fetal cardiac surgery and fetal bypass. Defining the mechanism by which placental vasopressin receptors respond to fetal bypass will permit reasonable application of available vasopressin antagonist therapy. This novel application may provide the fetal surgeon with a reasonable tool to translate application of fetal cardiac surgery to the clinic or improve fetal outcomes. The results could also translate into the world's first successful human fetal open-heart procedure. PUBLIC HEALTH RELEVANCE: Some of the 40,000 babies born every year in the United States with heart defects have defects so complex or life-threatening that these babies would benefit most from corrective open heart surgery performed when they are still in the womb. However, the ability to perform fetal open-heart surgery depends on providing cardiopulmonary bypass support during surgery without causing harm to the placenta. Using a standard sheep model our study will examine the use of medications that would protect the placenta during fetal open heart surgery. In this way we can perfect our techniques before attempting this procedure in human babies.